Cataract, or a clouding of the eye lens, is a condition affecting over half of all adults over the age of 80, with approximately 25 million patients suffering from the condition in the United States. Moreover, cataracts are thought to be the leading cause of blindness worldwide. αA-crystallin (cryAA) and αB-crystallin (cryAB) comprise thirty percent of the protein content of the eye lens, where they are responsible for maintaining lens transparency (Haslbeck et al., Nat Struct Mol Biol 12, 842 (2005). cryAA and cryAB belong to a family of small heat shock proteins (sHSPs) that contain a conserved crystallin domain (Bloemendal et al., Prog Biophys Mol Biol 86, 407 (2004); Haslbeck, supra). Once synthesized, these lens sHSPs are never degraded, so any damage accumulates through life and eventually leads to aging-associated cataract (Haslbeck, supra; Perng et al., J Biol Chem 274, 33235 (1999); Meehan et al., J Biol Chem 279, 3413 (2004); Meehan et al., J Mol Biol 372, 470 (2007)). Similarly, destabilizing mutations in cryAB, such as R120G, result in hereditary forms of cataract with early onset (Vicart et al., Nat Genet. 20, 92 (1998)). In hereditary cataract, cryAB is prone to aggregation and forms amyloid-like fibrils in vitro (Andley et al., PLoS One 6, e17671 (2011)).
Currently, treatment for cataracts includes surgery to excise the clouded lens and insert an artificial replacement. Surgery can be costly and is not appropriate for all patients. Therapies which target the underlying mechanism of protein aggregation would benefit these patients. Thus, there remains a need in the art for therapeutics and methods of screening for therapeutics that block aggregation-prone proteins, such as cryAB, from forming pathological aggregates (e.g., aggregates associated with cataracts).